Skip to main content
SpringerLink
Log in

A new approach in the treatment of hypotension in human septic shock by NG-monomethyl-L-arginine, an inhibitor of the nitric oxide synthetase

  • Brief Reports
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

NG-monomethyl-L-arginine (L-NMMA) is an inhibitor of the enzyme nitric-oxide-synthetase. Nitric oxide (NO), produced by endothelial and vascular cells regulates physiological vascular tone, blood pressure and tissue perfusion via guanylate-cyclase and cGMP. In an advanced stage of therapy resistant septic shock in response to inflammatory mediators, NO is overproduced. This leads to vasodilatation, a fall in systemic blood pressure and an attenuated vasoconstriction-response to sympathetic-stimuli. Two episodes of severe and prolonged hypotension in a patient with sepsis were successfully treated twice by bolus therapy of L-NMMA within 4 weeks. On both occasions blood pressure was reversed to normal and the continuous use of high doses of catecholamines were stopped. In contrast to the immediate response of blood pressure, heart rate and central venous pressure remained stable. Cardiac output dropped to 68% and PaO2 increased. These findings indicate that NO-synthetase-inhibitors may be of value in the therapy of human septic shock.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

  1. Ruokonen E, Takala J, Kari A, Alhava E (1991) Septic shock and multiple organ failure. Crit Care Med 19:1146–1151

    PubMed  Google Scholar 

  2. Vallance P, Leone A, Calver A, Collier J, Moncada S (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339:572–575

    PubMed  Google Scholar 

  3. Rees DD, Palmer RMJ, Moncada S (1989) Role of endothelium-derived nitric oxide in the regulation of blood pressure. Proc Natl Acad Sci USA 86:3375–3378

    PubMed  Google Scholar 

  4. Rees DD, Palmer RMJ, Schulz R, Hodson HF, Moncada S (1990) Characterisation of three inhibitors of endothelial nitric oxide synthetase in vitro and in vivo. Br J Pharmacol 101:746–752

    PubMed  Google Scholar 

  5. Hibbs JB, Taintor RR, Vavrin Z, Rachlin EM (1988) Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 157:87–94

    PubMed  Google Scholar 

  6. Moncada S, Palmar RMS, Higgs EA (1991) Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 43:109–142

    PubMed  Google Scholar 

  7. Evans T, Carpenter A, Cohen J (1992) Purification of a novel form of nitric oxide synthetase from rat liver. J Vasc Res 29:110

    Google Scholar 

  8. Buga GM, Gold ME, Fukuot JM, Ignarro (1991) Shear stress-induced release of nitric oxide from endothelial cells grown on beads. Hypertension 17:187–193

    PubMed  Google Scholar 

  9. Kim N, Vardi Y, Padma-Nathan H, Daley J, Goldstein I, Sanez de Teiada I (1992) Oxygen tension regulates nitric oxides synthesis: physiological role in erection. J Vasc Res 29:150

    Google Scholar 

  10. Vallance P, Collier J, Moncada S (1989) Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet II:997–1000

    Google Scholar 

  11. Ignarro LJ (1990) Nitric oxide, a novel signal tranduction mechanism for transcellular communication. Hypertension 16:477–483

    PubMed  Google Scholar 

  12. Dal Nogare AR (1991) Septic shock. Am J Med Sci 302:50–65

    PubMed  Google Scholar 

  13. Schmidt K, Werner ER, Mayer B, Wachter H, Kukovetz WR (1992) Tetrahydrobiopterin-dependant formation of endothelium-derived relaxing factor (nitric oxide) in arotic endothelial cells. Biochem J 281:297–300

    PubMed  Google Scholar 

  14. Liew FY, Cox FE (1991) Non-specific defence mechanism: the role of nitric oxide. Immunol Today 12:ALPHA-17-21

    Google Scholar 

  15. González MC, Fernández A, Martin C, Moncada S, Estrada C (1992) Endothelial and extra endothelial nitric oxide (NO) modulates vascular responses to sympathetic stimulation. J Vasc Res 29:121

    Google Scholar 

  16. Joulou-Schäffer G, Gray GA, Fleming I, Scott C, Parratt JR, Stoclet JC (1990) Loss of vascular responsiveness induced by endotoxin involves the L arginine pathway. Am J Physiol 259:1038–1043

    Google Scholar 

  17. Kilbourn RG, Gross SS, Jubran A (1990) NG-monomethyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci USA 87:3629–3632

    PubMed  Google Scholar 

  18. Sprague RS, Thiemermann C, Vane JR (1992) Endogenous nitric oxide maintains blood flow to hypoxic alveoli in anaesthetised rabbits. J Vasc Res 29:202

    Google Scholar 

  19. Kilbourn RG, Jubran A, Gross SS, Griffith OW, Levi R, Adams J, Lodato RF (1990) Reversal of endotoxin-mediated septic shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun 172:1132–1138

    PubMed  Google Scholar 

  20. Thiemermann C, Vane J (1990) Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolisacherides in the rat in vivo. Eur J Pharmacol 182:591–595

    PubMed  Google Scholar 

  21. Geroulanos S, Schilling J, Cakmakci M, Jung H, Largiadèr F (1992) Inhibition of NO synthesis in septic shock. Lancet (letter) 339:435

    Google Scholar 

  22. Petros A, Bennett D, Vallance P (1991) Effect of nitric oxide synthtease inhibitors on hypotension in patients with septic shock. Lancet 338:1557–1558

    PubMed  Google Scholar 

  23. Vidal MJ, Zocci MR, Poggi A, Chierchia S (1992) Involvement of the NO-inducible pathway in Tumor-cell adhesion to vascular endothelium. J Vasc Res 29:220

    Google Scholar 

  24. Lee TJF, Chen FY (1992) Release of nitric oxide in cerebral neurogenic vasodilatation. J Vasc Res 29:156

    Google Scholar 

  25. Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ (1992) Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med 326:90–94

    PubMed  Google Scholar 

  26. Mitchell JA, Warner TD, Huang ZJ, Förstermann U, Murad F (1992) Native LDL inhibits the release of endothelial derived relaxing factor by reducing the activity of endothelial nitric oxide synthetase. J Vasc Res 29:169

    Google Scholar 

  27. Pohl U, Galle J (1992) Low density lipoproteins attenuated bradykinine and L-arginine-induced increase of cGMP in cultured endothelial cells. J Vasc Res 29:183

    Google Scholar 

  28. Mayer B, Heinzel B, Klatt P, John M, Schmidt K, Böhme E, Kukovetz WR (1992) No synthetase-catalysed activation of oxygen and reduction of cytochromes: reaction mechanisms and possible physiological implications. J Vasc Res 29:164

    Google Scholar 

  29. McGrath JC, Bulloch JM (1992) A neuromodulatory role for nitric oxide in sympathetic neuroeffector responses. J Vasc Res 29:165

    Google Scholar 

  30. Shaw A, MacLean MR, Pollock D, McGrath JM (1992) Influence of L-NAME on alpha-1- and alpha-2-adenoreceptor responses in the isolated rabbit pulmonary artery and the rat krebs-perfused lung. J Vasc Res 29:197

    Google Scholar 

  31. Feelisch M, Bloch W, Reinhardt M, Addicks K (1992) Nitric oxide modulates peripheral sympathetic activity in the myocardium. J Vasc Res 29:112

    Google Scholar 

  32. Hotchkiss RS, Karl IE, Parker JP, Adams HR (1992) Inhibition of NO synthesis in septic shock. Lancet (letter) 339:434

    Google Scholar 

  33. Takahashi H, Nakanishi T, Nishimura M, Tanaka H, Yoshimura M (1992) Serum levels of nitrite and nitrate ions significantly correlate with blood pressure in women. J Vasc Res 29:210

    Google Scholar 

  34. Gurevich VS, Mickailova IA, Bondarenco BB (1992) The platelet function test for simple and rapid estimation of EDRF activity in the clinic. J Vasc Res 29:127

    Google Scholar 

  35. Gross SS, Levi R, Xu Y (1992) LPS induces tetrahydrobiopterin synthesis in vascular smooth muscle: The rate-limiting factor for induction of nitric oxide. J Vasc Res 29:125

    Google Scholar 

  36. Lundberg JM, Weitzberg E, Alving K, Rudehill A (1992) Nitric oxide inhalation causes vasodilatation in bronchial and pulmonary circulation and attenuates pulmonary endotoxin effect. J Vasc Res 29:161

    Google Scholar 

  37. McMahon TJ, Hood JS, Kadowitz PJ (1992) Pulmonary vasodilator response to vagal stimulation is blocked by N-omega-nitro-L-arginine methyl ester in the cat. Circ-Res 70:364–369

    PubMed  Google Scholar 

  38. Persson MG, Gustafsson LE, Wiklund NP, Moncada S, Hedqvist P (1990) Endogenous nitric-oxide as a probable modulator of pulmonary circulation and hypoxic presser response in vivo. Acta Physiol Scand 140:449–457

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, University Hospital Zürich, Rämistrasse100, CH-8091, Zürich, Switzerland

    J. Schilling, M. Cakmakci &  S. Geroulanos

  2. Department of Anaesthesiology, University Hospital Zürich, Rämistrasse 100, CH-8091, Zürich, Switzerland

    U. Bättig

Authors
  1. J. Schilling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Cakmakci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. U. Bättig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Geroulanos
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schilling, J., Cakmakci, M., Bättig, U. et al. A new approach in the treatment of hypotension in human septic shock by NG-monomethyl-L-arginine, an inhibitor of the nitric oxide synthetase. Intensive Care Med 19, 227–231 (1993). https://doi.org/10.1007/BF01694775

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01694775

Key words

Search

Navigation